Postural tachycardia syndrome (POTS) often afflicts younger CFS patients. We classified POTS patients into three flow regimes - low, normal, and high flow based on supine blood flow. Data suggest the involvement of nitric oxide (NO) and angiotensin in producing redistributive hypovolemia and sympathoexcitation. The overall objective of the application is to define mechanisms of CFS/POTS related to bioavailable NO, and to explore the subclinical microvascular abnormalities in CFS without POTS (CFS/~POTS). We will subset CFS patients (16-29 years) by POTS using upright tilt, and subgroup POTS based on peripheral blood flow. We will compare low flow POTS (N=30) and normal flow POTS (N=30), to CFS/~POTS (N=30) and control (N=30) with and without POTS to explore the following hypotheses: 1) Low flow CFS/POTS is due to decreased bioavailable NO produced by nNOS related to increased angiotensin-II (A-II) and oxidative stress. This increases isoprostanes, 3- nitrityrosine, and IL-6 increasing angiotensinogen. We will measure skin blood flow with laser flowmetry, NO and its metabolites by intradermal microdialysis, and use local heating (nNOS dependent) and acetylcholine response (eNOS dependent) combined with isoform selective NOS inhibitors to demonstrate isoform dependence of low flow CFS/POTS. We will test whether A-II receptor blocker, losartan, corrects cutaneous flow. 2) Oral losartan increases regional circulation and cutaneous microvascular NO dependent responses in low flow CFS/POTS. We will simultaneously measure regional blood flows/volumes, and perform cutaneous local heating and acetylcholine before and after losartan administration in low flow CFS/POTS patients. 3) NO is increased in normal flow CFS/POTS producing nitrosative stress. As in 1) we will measure NO and use local heating and acetylcholine response combined with isoform selective NOS inhibitors to ascertain isoform dependence of normal flow CFS/POTS. Cutaneous somatostatin administration can reduce skin NO excess. 4) Subcutaneous octreotide, a somatostatin analog, reduces orthostatic splanchnic pooling and cutaneous microvascular NO dependent responses in normal flow CFS/POTS. We will smeasure changes in regional blood flows and blood volumes, and perform cutaneous local heating and acetylcholine dose-response before and after octreotide administration and during tilt in normal flow CFS/POTS patients. Blood flow abnormalities associated with the postural tachycardia syndrome (POTS) produce major disability in younger CFS patients. These may be due to defects in a fundamental signaling molecule called nitric oxide (NO). In the current application we will determine how NO produces POTS in CFS patients and whether drugs that alter NO can improve patient health. [unreadable] [unreadable] [unreadable]